Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity
Abstract Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular links remain elusive. Here, we explore this crosstalk using triple-negative breast cancer (TNBC) as a model, a subtype often prone to DNA damage accumulation. We show that the de novo purine synt...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53877-z |
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| author | Lorena Espinar Marta Garcia-Cao Alisa Schmidt Savvas Kourtis Antoni Gañez Zapater Carla Aranda-Vallejo Ritobrata Ghose Laura Garcia-Lopez Ilir Sheraj Natalia Pardo-Lorente Marina Bantulà Laura Pascual-Reguant Evangelia Darai Maria Guirola Joan Montero Sara Sdelci |
| author_facet | Lorena Espinar Marta Garcia-Cao Alisa Schmidt Savvas Kourtis Antoni Gañez Zapater Carla Aranda-Vallejo Ritobrata Ghose Laura Garcia-Lopez Ilir Sheraj Natalia Pardo-Lorente Marina Bantulà Laura Pascual-Reguant Evangelia Darai Maria Guirola Joan Montero Sara Sdelci |
| author_sort | Lorena Espinar |
| collection | DOAJ |
| description | Abstract Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular links remain elusive. Here, we explore this crosstalk using triple-negative breast cancer (TNBC) as a model, a subtype often prone to DNA damage accumulation. We show that the de novo purine synthesis enzyme IMPDH2 is enriched on chromatin in TNBC compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent, and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts with and modulates PARP1 activity by controlling the nuclear availability of NAD+ to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2, acting as a convergence point of nuclear metabolism and DNA damage response. |
| format | Article |
| id | doaj-art-0fd2c3a7be624c68af7c1b6ba8b07ae7 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-0fd2c3a7be624c68af7c1b6ba8b07ae72024-11-17T12:36:55ZengNature PortfolioNature Communications2041-17232024-11-0115112010.1038/s41467-024-53877-zNuclear IMPDH2 controls the DNA damage response by modulating PARP1 activityLorena Espinar0Marta Garcia-Cao1Alisa Schmidt2Savvas Kourtis3Antoni Gañez Zapater4Carla Aranda-Vallejo5Ritobrata Ghose6Laura Garcia-Lopez7Ilir Sheraj8Natalia Pardo-Lorente9Marina Bantulà10Laura Pascual-Reguant11Evangelia Darai12Maria Guirola13Joan Montero14Sara Sdelci15Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat de BarcelonaCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat de BarcelonaCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88Abstract Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular links remain elusive. Here, we explore this crosstalk using triple-negative breast cancer (TNBC) as a model, a subtype often prone to DNA damage accumulation. We show that the de novo purine synthesis enzyme IMPDH2 is enriched on chromatin in TNBC compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent, and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts with and modulates PARP1 activity by controlling the nuclear availability of NAD+ to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2, acting as a convergence point of nuclear metabolism and DNA damage response.https://doi.org/10.1038/s41467-024-53877-z |
| spellingShingle | Lorena Espinar Marta Garcia-Cao Alisa Schmidt Savvas Kourtis Antoni Gañez Zapater Carla Aranda-Vallejo Ritobrata Ghose Laura Garcia-Lopez Ilir Sheraj Natalia Pardo-Lorente Marina Bantulà Laura Pascual-Reguant Evangelia Darai Maria Guirola Joan Montero Sara Sdelci Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity Nature Communications |
| title | Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity |
| title_full | Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity |
| title_fullStr | Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity |
| title_full_unstemmed | Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity |
| title_short | Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity |
| title_sort | nuclear impdh2 controls the dna damage response by modulating parp1 activity |
| url | https://doi.org/10.1038/s41467-024-53877-z |
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